Nicholson et al. U.S. Pat. No. 3,385,886 claims 2-(4-isobutylphenyl)propionic acid (ibuprofen) as a compound per se. Nicholson et al. U.S. Pat. No. 3,228,831 discloses the use of ibuprofen as a drug to alleviate the symptoms of inflammation in animals. Since its introduction as a commercially available drug for human use, there has been much medical literature about ibuprofen. Ibuprofen is sold as coated tablets because ibuprofen per se has a bitter, sharply disagreeable taste. The distinct acid taste of ibuprofen is masked by the coating which permits oral administration without giving the bitter or burning acid taste of the free acid. Continued research for better modes in which to administer ibuprofen continues for the purposes of eliminating or reducing the cost of and the need for coatings presently used to overcome as much as possible the disagreeable acid taste of ibuprofen.
It has been found that the usual sodium, calcium and magnesium salts of this acid also contain a discernible disagreeable taste.
Recently, it was discovered that aluminum salts of ibuprofen provide an essentially tasteless, effective pharmaceutical form of ibuprofen which salts can be manufactured economically and compounded into pharmaceutical liquid suspension and solid formulations for administration in unit dosage forms. These aluminum salts are disclosed and claimed in Sinkula U.S. patent application Ser. No. 640,431, filed Dec. 15, 1975, now abandoned but replaced by application Ser. No. 152,238, filed May 22, 1980.
Aluminum ibuprofen salts are not soluble in water or the other pharmaceutical excipients to any substantial extent and they are difficult to wet and disperse uniformly in liquid mixtures. These salts would normally be compounded into any of various solid dosage forms. However, pharmaceutical liquid suspension forms of these salts would be preferred when the patients are to be small children or elderly persons because these patient populations often have difficulty swallowing tablets, capsules or other solid forms of drugs.
In preparing suspensions of water-insoluble drug compounds such as these aluminum ibuprofen salts, the particular pharmaceutical vehicle or diluent mixture which is best for these salts is not readily predictable from knowledge and experience with other similar drug acid salts. Substitution of an aluminum salt of one drug acid into a pharmaceutical formulation of another aluminum salt of a drug acid does not often produce an acceptable pharmaceutical composition for the dosage use intended. See, for example, Belgian Pat. No. 811,810 and the results obtained comparing that formulation in Fitch/Rowe U.S. Pat. No. 4,145,440, Column 9.
To be an acceptable pharmaceutical product the aluminum ibuprofen salt suspension must have a suitable long shelf life, say, one to three years, the liquid suspension must not gel to any significant extent, the solids in the liquid suspension must not settle to form a hard non-uniformly dispersible cake, and the amount of sedimentation of the solids in the suspension must be controlled to within a range of from about 60 to 95 percent of the suspension liquid volume, preferably to about 70 to 85 percent of the suspension liquid volume.
This invention can be considered to be an improvement on the aluminum ibuprofen pharmaceutical suspensions described and claimed in the Fitch/Rowe U.S. Pat. No. 4,145,440. That Fitch/Rowe '440 Patent described pharmaceutical liquid suspension compositions of aluminum ibuprofen salts which are gel-resistant, non-caking, have controlled sedimentation properties and which are easily re-suspended by shaking the suspension bottle by dispersing the aluminum ibuprofen salt in a sorbitol/glycerin/water mixture containing controlled maximum amounts of pharmaceutically acceptable suspending agents and water-soluble surface active agents. Those Fitch/Rowe '440 Patent compositions can also contain small amounts of ethanol, sorbic acid, and sweetening agents such as sucrose, sodium saccharin, and flavoring and coloring agents. Such patent also includes discussion of using an aluminum ibuprofen salt having a ratio of about two ibuprofen equivalents per atom of aluminum in the salt.
Those Fitch/Rowe '440 Patent compositions are effective when used shortly after preparation thereof. However, unexpectedly, it has been discovered that upon long standing on a shelf at various temperature conditions, a problem with those compositions has been observed, the problem being that such Fitch/Rowe '440 compositions, based as they are on a sorbitol/glycerin mixture as part of the liquid vehicle for the suspension, exhibit an aging property of the resulting composition. This aging property has the effect of reducing the dissolution rate of the active ingredient, the aluminum ibuprofen salt, in the liquid suspension to an unacceptably low percentage level when an extended shelf life (say six months or longer) is required for clinical or market acceptance of the suspension as desired product for use world wide for pediatric and geriatric anti-inflammatory therapy applications, which circumstances often require long storage times under varying temperature environments.
Finding this catalytic effect on aging of the composition by the sorbitol/glycerin components in the composition was surprising because there are pharmaceutical literature references such as "Structure of Aluminum Hydroxide Gel III: Mechanisms of Stabilization by Sorbitol" by Steven L. Nail et al. in Journal of the Pharmaceutical Sciences, Vo. 65, No. 8, August 1976 pgs. 1195-1198, which indicate that sorbitol, added to aluminum hydroxide gels, was effective in preventing the loss of the acid consuming capacity of the gel (less than ten percent loss) during the six month aging periods, compared to the substantial loss (greater than sixty percent loss) of acid consuming capacity of identical gels which did not contain sorbitol. However, in these aluminum ibuprofen pharmaceutical suspensions it has been found, according to this invention, that sorbitol and glycerin, for some reason not yet fully understood, appear to catalyze the aging and to reduce the dissolution rates of aluminum ibuprofen in these pharmaceutical suspensions. Those in the pharmaceutical chemistry sciences and arts continue to need and search for liquid pharmaceutical suspensions of aluminum ibuprofen salts which are not only gel resistant, non-caking, have controlled sedimentation properties and which suspensions are easily resuspended by shaking the suspension bottle, but also for liquid pharmaceutical suspensions which will not contain ingredients which lower to unacceptable levels the dissolution rate properties of the aluminum ibuprofen contained therein during normal storage periods.